This invention relates to methods and devices for the site-specific delivery of bioactive agents in mammals, especially for cardiac and peripheral vascular applications, and more particularly, as respects application for coronary thrombolysis and revascularization procedures, to methods and devices for prevention of coronary vasoconstriction, vascular thrombosis and restenosis during and after percutaneous transluminal coronary angioplasty and for prevention of coronary artery bypass graft thrombosis and occlusion.
1. Pathophysiological Background
A. Vascular Endothelium Function PA0 B. Vascular Stenosis PA0 C. Coronary Artery Stenosis PA0 A. Procedures PA0 B. The Problem of Vascular Restenosis
Normal blood vessels are lined with a layer of endothelial cells. The endothelium releases local factors (endothelium-derived relaxing factor [nitric oxide] and prostaglandin I.sub.2 [PGI.sub.2, or prostacyclin]) into the vessel wall (intramural release) and into the blood stream (intraluminal release). These factors maintain vascular tone (vessel relaxation), inhibit clot formation on the vessel inner surface (platelet adhesion and aggregation), inhibit monocyte adherence and chemotaxis, and inhibit smooth muscle cell migration and proliferation. Normal endothelium releases both prostacyclin and nitric oxide in response to platelet aggregation. Nitric oxide release inhibits platelet adhesion, prevents further aggregation, and promotes platelet disaggregation. Prostacyclin release, promoted by platelet-derived thromboxane A.sub.2, acts synergistically with nitric oxide to prevent platelet-mediated vasoconstriction. As a result of this process, vasodilation and thrombolysis occurs, and blood flow is maintained. If the endothelium is dysfunctional or damaged, however, nitric oxide and prostacyclin release is impaired. Platelet aggregation and adhesion can occur unopposed, with platelet-derived products acting directly on the smooth muscle cells to cause vasoconstriction. The net result is a blood vessel which is highly susceptible to thrombosis and vasospasm. See, "Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor", Palmer R., et al., NATURE, 327:524, 1987; "Control of coronary vascular tone by nitric oxide", Kelm M., et al., CIRC. RES., 66:1561, 1990; "Regulatory functions of the vascular endothelium", Vane J., et al., N. ENCL. J. MED., 323:27, 1990; "Endothelial modulation of vascular tone: Relevance to coronary angioplasty and restenosis", Harrison D., J. AMER. COL. CARDIOL., 17:71B, 1991; "The antiaggregating properties of vascular endothelium: Interactions between prostacyclin and nitric oxide", Radomski M., et al., BRIT. J. PHARMACOL., 92:639, 1987; "EDRF increases cyclic GMP in platelets during passage through the coronary vascular bed", Pohl U., et al., CIRC. RES., 65:1798, 1989; "Human endothelial cells inhibit platelet aggregation by separately stimulating platelet cAMP and cGMP", Alheid U., et al., EUROP. I. PHARMACOL., 164:103, 1989; "Nitric oxide: An endogenous modulator of leukocyte adhesion", Kubes P., et al., PROC. NATL. ACAD. SCI., 88:4651, 1991; "Nitric oxide and prostacyclin: Divergence of inhibitory effects on monocyte chemotaxis and adhesion to endothelium in vitro", Bath P., et al., ARTERIOSCLER. THROMB., 11:254, 1991; "Nitric oxide generating vasodilators and 8-Br-cGMP inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells", Garg U., et al., J. CLIN. INVEST., 83:1774, 1989; "Role of blood platelets and prostaglandins in coronary artery disease", Mehta J., et al., AMER. J. CARDIOL., 48:366, 1981; and "Prostaglandins and cardiovascular disease: A review", Jacobsen D., SURGERY, 93:564, 1983.
Atherosclerosis can form within a blood vessel over a period of years from a variety of causes. The resulting lesion, or plaque, may progressively occlude the vessel and impede blood flow to vital organs. The stenotic lesions when covered by endothelium are termed stable. See, "Cellular proliferation in atherosclerosis and hypertension", Schwartz S., et al., PROG. CARDIOVASC. DIS., 26:355, 1984; and "The pathogenesis of atherosclerosis: An update", Ross R., N. ENGL. J. MED., 314:488, 1986.
Unstable stenotic lesions are associated with endothelial cell injury at the sites of coronary stenosis. Injury to the endothelium stops the local release of the endothelium-derived factors. Severe injury to the vessel wall exposes the underlying collagen layer, which immediately activates platelet adhesion and aggregation (clumping) and stimulates vasoconstriction (spasm). The platelet blood clotting cascade is triggered, thrombin and fibrin quickly form at the site(s) of vascular injury, and a thrombus begins forming. The aggregating platelets release local growth factor (platelet-derived growth factor or PDGF) which activates smooth muscle cells within the vessel wall. Over a period of days-to-weeks, smooth muscle cells migrate into the thrombus and proliferate, and the thrombus becomes organized. See, "The restenosis paradigm revisited: An alternative proposal for cellular mechanisms", Schwartz R., et al., J. AMER. COL. CARDIOL., 20:1284, 1992; "The pathogenesis of coronary artery disease and the acute coronary syndromes: Parts I and II", Fuster V., et al., N. ENCL. J. MED., 326:242 and 310, 1992; "Migration of smooth muscle and endothelial cells", Casscells W., CIRC., 86:723, 1992; "The role of platelets, thrombin and hyperplasia in restenosis after coronary angioplasty", Ip J., et al., J. AMER. COL. CARDIOL., 17:77B, 1991; "Syndromes of accelerated atherosclerosis: Role of vascular injury and smooth muscle cell proliferation", Ip J., et al., J. AMER. COL. CARDIOL., 15:1667, 1990; "Time course of smooth muscle cell proliferation in the intima and media of arteries following experimental angioplasty", Hanke H., et al., CIRC. RES., 67:651, 1990; "Effect of platelet factors on migration of cultured bovine aortic endothelial and smooth muscle cells", Bell L., et al., CIRC. RES., 65:1057, 1989; "Role of platelets in smooth muscle cell proliferation and migration after vascular injury in rat carotid artery", Fingerle J., et al., PROC. NATL. ACAD. SCI., 86:8412, 1989; "Restenosis after coronary angioplasty: Potential biologic determinants and role of intimal hyperplasia", Liu M., et al., CIRC., 79:1374, 1989; "Is vasospasm related to platelet deposition?", Lam J., et al., CIRC., 75:243, 1988; "Role of platelets and thrombosis in mechanisms of acute occlusion and restenosis after angioplasty", Harker L., AMER. J. CARDIOL., 60:20B, 1987; and "Restenosis after arterial angioplasty: A hemorrheologic response to injury", Chesebro J., et al., AMER. J. CARDIOL., 60:10B, 1987.
The described vasoconstrictive physiologic mechanisms occur both in peripheral and in coronary arteries, but the consequences of the processes are more life threatening in the coronary arteries. Coronary arteries, the arteries of the heart, perfuse the cardiac muscle with oxygenated arterial blood. They provide essential nutrients and allow for metabolic waste and gas exchange. These arteries are subject to unremitting service demands for continuous blood flow throughout the life of the patient. A severe proximal coronary artery stenosis with endothelial injury induces cyclic coronary flow reductions ("CFR's"). These are periodic or spasmodic progressive reductions in blood flow in the injured artery. Episodes of CFR's are correlated to clinical acute ischemic heart disease syndromes, which comprise unstable angina, acute myocardial infarction and sudden death. The common pathophysiologic link is endothelial injury with vasospasm and/or thrombus formation.
Coronary artery disease is the leading cause of death in the United States today. In 1992, the clinical population of unstable angina patients in the United States numbered approximately 1,000,000. Of these patients, it is estimated that 160,000 underwent coronary thrombolysis therapy where a clot dissolving agent is injected intravenously or intracoronary to reopen the thrombosed vessel and reduce the incidence of myocardial infarction and sudden death. See, "Mechanisms contributing to precipitation of unstable angina and acute myocardial infarction: Implications regarding therapy", Epstein S., et al., AMER. J. CARDIOL., 54:1245, 1984; "Unstable angina with fatal outcome: Dynamic coronary thrombosis leading to infarction and/or sudden death", Falk E., CIRC., 71:699, 1985; "Speculation regarding mechanisms responsible for acute ischemic heart disease syndromes", Willerson J., et al., J. AMER. COL. CARDIOL., 8:245, 1986; "Platelets and thrombolytic therapy", Coller B., N. ENGL. J. MED., 322:33, 1990; and "Frequency and severity of cyclic flow alterations and platelet aggregation predict the severity of neointimal proliferation following experimental coronary stenosis and endothelial injury", Willerson J., et al., PROC. NATL. ACAD. SCI., 88:10624, 1991.
2. Surgical Procedures for Coronary Artery Disease
Historically, the treatment of advanced atherosclerotic coronary artery disease (i.e., beyond that amenable to therapy via medication alone) has involved cardiac surgery in the form of a coronary artery bypass graft ("CABG"). The patient is placed on cardiopulmonary bypass (heart-lung machine) and the heart muscle is temporarily stopped (cardioplegia). Repairs are then surgically affected on the heart in the form of detour conduit grafted vessels (vein or artery graft) providing blood flow around the coronary artery obstruction(s). While CABG surgery has been shown to be effective, it carries with it inherent surgical risk and requires a recuperation period of several weeks. During 1992, approximately 290,000 patients underwent CABG surgery in the United States.
A major advance in the treatment of atherosclerotic coronary artery disease occurred in the late 1970's with introduction of the less-invasive percutaneous transluminal coronary angioplasty ("PTCA") procedures. The PTCA technique involves the retrograde introduction, from an artery in the leg or arm, up to the area of coronary vascular stenosis, of a catheter with a small dilating balloon at its tip. The catheter is advanced through the arteries via direct fluoroscopic guidance and passed across the luminal narrowing of the vessel. Once in place the catheter balloon is inflated for a short period of time. This results in mechanical deformation of the lesion or vessel with a subsequent increase in the cross-sectional area. This in turn reduces obstruction and transluminal pressure gradients, and increases blood flow through the coronary artery. PTCA or angioplasty is a term that now may include other percutaneous transluminal methods of decreasing stenosis within a blood vessel, and includes not only balloon dilation, but also thermal ablation and mechanical atherectomy with shaving, extraction or ultrasonic pulverization of the lesion. During 1992 in the United States, it is estimated that some 400,000 patients underwent coronary angioplasty procedures.
Despite the major therapeutic advances in the treatment of coronary artery disease represented by thrombolytic therapy, CABG operations and PTCA procedures, the success of these measures has been hampered by the development of vessel renarrowing or reclosure, most significantly in patients undergoing thrombolysis and angioplasty procedures. Abrupt vessel occlusion or early restenosis may develop during a period of hours to days post-procedure due to vasospasm and/or platelet thrombus formation at the site of vessel injury. The more common and major limitation, however, is a development of progressive reversion of the diseased vessel to its previous stenotic condition, negating any gains achieved from the procedure. This gradual renarrowing process is referred to as restenosis or intimal hyperplasia. Restenosis is a reparative response to endovascular injury after angioplasty and in vein grafts following vessel bypass surgery. The sequence of events is similar to that described above for unstable lesions associated with endothelial injury, progressing through the process of platelet aggregation, vasoconstriction, thrombus formation, PDGF release, smooth muscle cell proliferation, and thrombus organization.
Clinical studies indicate that thrombolytic therapy is ineffective in about 20% of the treated patients and that 20% of those patients initially responding to therapy develop vessel rethrombosis within one week. Clinical studies also indicate that significant restenosis occurs in about 40% of the PTCA patients within six months and in about 20% of the CABG patients within one year. This complication results in increased morbidity, need for repeating the procedure, and escalating medical costs. With an estimated 690,000 coronary revascularization procedures performed in the United States in 1992, these incidences mean as many as 200,000 patients may develop vessel restenosis within one year after operation. Repeat procedures could account for $2.85 billion in additional health care costs in the United States.
6. Lack of Success in Prevention of Vasular Restenosis Without Side-Effects
At present, no therapy is know that consistently prevents the major clinical problem of vascular restenosis. Intravenous medications have been tried as a means to prevent PTCA restenosis and other coronary disease syndromes. Systemically administered pravastatin (U.S. Pat. No. 4,346,227) and lovastatin (U.S. Pat. No. 5,140,012), both HMG CoA reductase inhibitors, have been said to prevent restenosis following angioplasty. Prostaglandin E.sub.1 ("PGE.sub.1 ", a congener of endothelium-derived PGI.sub.2 and prostacyclin) and a known potent vasodilator with antiplatelet, antiinflammatory and antiproliferative effects--see "Hemodynamic effects of prostaglandin E.sub.1 infusion in patients with acute myocardial infarction and left ventricular failure", Popat K., et al., AMER. HEART J., 103:485, 1982; "Comparison of equimolar concentrations of iloprost, prostacyclin, and prostaglandin E.sub.1 on human platelet function", Fisher C., et al., J. LAB. CLIN. MED., 109:184, 1987; and "Prostaglandin E.sub.1 inhibits DNA synthesis in arterial smooth muscle cells stimulated with platelet-derived growth factors", Nilsson J., et al., ATHEROSCLEROSIS, 53:77, 1984--has been reported to inhibit abrupt occlusion and early restenosis in patients when infused intravenously after PTCA for 12 hours at dosages of from 20 to 40 ng/kg/min following a 65 ng bolus given intracoronary before and after PTCA, "Prostaglandin E.sub.1 infusion after angiolplasty in humans inhibits abrupt occlusion and early restenosis", See J., et al., ADV. PROSTAGLANDIN, THROMBOXANE AND LEUKOTRIENE RES., 17:266, 1987. However, prostacyclin (PGI.sub.2) did not lower the coronary restenosis rate at 5 months following PTCA, although infused intravenously for 48 hours after PTCA at dosages of 5.0 ng/kg/min following intracoronary infusion at 7.0 ng/kg/min before and after the PTCA procedure, "Effect of short-term prostacyclin administration on restenosis after percutaneous transluminal coronary angioplasty", Knudtson M., et al., J. AMER. COL. CARDIOL., 15:691, 1990.
Sodium nitroprusside and other organic nitrates including nitroglycerin have long been used as vasodilator agents, and investigations, cited above, have shown that nitric oxide is the endogenous endothelium-derived nitrovasodilator: These agents also have anti-platelet effects, "The interaction of sodium nitroprusside with human endothelial cells and platelets: Nitroprusside and prostacyclin synergistically inhibit platelet function", Levin R., et al., CIRC., 66:1299, 1982; "Platelets, vasoconstriction, and nitroglycerin during arterial wall injury: A new antithrombotic role for an old drug", Lam J., et al., CIRC., 78:7122, 1988. In a study in stenosed and endothelium-injured canine coronary arteries, promotion of endogenous nitric oxide production by infusion of L-arginine (the precursor for nitric oxide synthesis), at a dosage of 60 mg/kg, decreased platelet aggregation and abolished CFR's, "Endogenous nitric oxide protects against platelet aggregation and cyclic flow variations in stenosed and endothelium-injured arteries", Yao S., et al., CIRC., 86:1302, 1992. Intravenous nitroglycerin infusion at dosages from 10 to 15 .mu.g/kg/min inhibited CFR's in stenosed and endothelium-injured coronary arteries of dogs. This effect was potentiated by the pretreatment with the reduced thiol, N-acetylcysteine, at a dose of 100 mg/kg for 30 minutes, "Intravenous nitroglycerin infusion inhibits cyclic blood flow responses caused by periodic platelet thrombus formation in stenosed canine coronary arteries", Folts J., et al., CIRC., 83:2122, 1991. Sodium nitroprusside is also a nitric oxide donor agent, "Metabolic activation of sodium nitroprusside to nitric oxide in vascular smooth muscle", Kowaluk E., et al., J. PHARMACOL. EXPER. THERAPEUTICS, 262:916, 1992.
The difficulty with systemic infusion of PGE.sub.1, PGI.sub.2, prostacyclin, sodium nitroprusside and the other organic nitrates is that, in dosages high enough to provide signs of beneficial cardiac effect, the potent vasodilator and antiplatelet effects of these bioactive agents also produce systemic side effects of bleeding and hypotension. No know therapy consistently prevents acute coronary thrombosis and chronic vascular restenosis while reducing the systemic side-effects of bleeding and hypotension. See, "Prevention of restenosis after percutaneous transluminal coronary angioplasty: The search for a `magic bullet`", Hermans W., et al., AMER. HEART J., 122:171, 1991; and "Clinical trials of restenosis after coronary angioplasty", Popma J., et al., CIRC., 84:1426, 1991.
Recently, site-specific drug delivery to the arterial wall has become a new strategy for the treatment of vascular diseases, including vessel restenosis following PTCA. These drug delivery systems include: (1) intravascular devices for site-specific (coronary artery) drug delivery comprising double-balloon catheters, porous balloon catheters, microporous balloon catheters, channel balloon catheters, balloon over stent catheters, hydrogel coated balloon catheters, iontophoretic balloon catheters and stent devices; (2) periadventitial and epicardial drug delivery devices, requiring surgical implantation, which include drug-eluting polymer matrices and a iontophoretic patch device; and (3) intramural injection of drug-eluting microparticles. All of these methods are limited by certain problems including additional trauma to the vessel wall, rapid washout of drug, need for invasive insertion, and/or use of therapeutic agents having a single mechanism of action. See, "Effect of controlled adventitial heparin delivery on smooth muscle proliferation following endothelial injury", Edelman E., et al., PROC. NATL. ACAD. SCI., 87:3773, 1990; "Localized release of perivascular heparin inhibits intimal proliferation after endothelial injury without systemic anticoagulation", Okada T., et al., NEUROSURGERY, 25:892, 1989; "Iontophoretic transmyocardial drug delivery: A novel approach to antiarrhythmic drug therapy", Avitall B., et al., CIRC., 85:1582, 1992; "Direct intraarterial wall injection of microparticles via a catheter: A potential drug delivery strategy following angioplasty", Wilensky R., et al., AMER. HEART J., 122:1136, 1991; "Local anticoagulation without systemic effect using a polymer heparin delivery system", Okada T., et al., STROKE, 19:1470, 1988.
Intrapericardial injection of drugs has been used for the treatment of malignant or loculated pericardial effusions in man. Drugs that have been injected into the pericardial space include antibiotic, antineoplastic, radioactive and fibrinolytic agents. This method of site-specific drug delivery has been shown to be effective in attaining higher, longer-lasting drug levels in the pericardial fluid with lower plasma concentrations and less systemic toxicity. It has been reported that no major complications were associated with the intrapericardial drug infusion catheter and that it was possible to repeat the procedure without difficulty. See, "Intrapericardial instillation of platin in malignant pericardial effusion", Fiorentino M., et al., CANCER, 62:1904, 1988; and "Use of streptokinase to aid drainage of postoperative pericardial effusion", Cross J., et al., BRIT. HEART J., 62:217, 1989.